Drug Interaction Report

MONITOR: Coadministration with levacetylleucine may increase the plasma concentrations (AUC) and adverse effects of drugs that are substrates of the P-glycoprotein (P-gp) efflux transporter. Levacetylleucine is a P-gp inhibitor in vitro. However, clinical data are not available.

MANAGEMENT: If coadministration is clinically necessary, more frequent clinical monitoring for P-gp substrate related adverse reactions is advised and dose adjustments may be required, particularly when levacetylleucine is initiated or withdrawn from concomitant therapy. Consultation with package labeling of the concomitant medication may be advisable.

ADJUST DOSE: Smoking may decrease the plasma concentrations of riociguat. The proposed mechanism is induction of the CYP450 1A1-mediated metabolism of riociguat by polycyclic aromatic hydrocarbons present in cigarette smoke. CYP450 1A1 is responsible for the formation of the major active metabolite, M1, which has just 1/3 to 1/10 the pharmacologic activity of riociguat. According to the product labeling, plasma concentrations of riociguat are reduced by 50% to 60% in smokers compared to nonsmokers.

MANAGEMENT: Patients should be advised to stop smoking. Riociguat dosages higher than 2.5 mg three times a day may be considered in cigarette smokers, if tolerated, to match the exposure seen in nonsmoking patients. However, safety and effectiveness of higher dosages have not been established. A dosage reduction should be considered in patients who stop smoking during treatment with riociguat. The tablet form of riociguat can generally be taken with or without food. Some authorities recommend not to switch between fed and fasted riociguat intake because of increased peak plasma levels of riociguat in the fasting compared to the fed state.